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REVIEW

Selenium: Its and relation to exercise

Abdulkerim Kasim Baltaci1*, Rasim Mogulkoc1, Mustafa Akil2 and Mursel Bicer3 1Selcuk University, Selcuklu Medical School, Department of Physiology, Konya, Turkey 2Karabuk University, High School of Physical Education and Sport, Karabuk, Turkey 3Selcuk University, High School of Physical Education and Sport, Konya, Turkey

Abstract: (Se), which is commonly found in nature, is one of the essential trace elements necessary for the normal development of human and animal . Selenium was first defined in 1818 by the Swedish chemist Berzelius in sulfuric acid residues. At the end of 1960s, the role of selenium in human health began to attract attention and human diseases that resembled animal diseases responding to selenium was started to be investigated. Selenium, which is highly important for human health, is necessary for a variety of metabolic processes, including thyroid hormone metabolism, protection against and immunity functions. Selenium is a molecule that activates peroxidase, and thus, it is involved in the antioxidant mechanisms that prevent oxidant damage. Exhaustive physical exercise is known to cause oxidant damage, probably by promoting free production in many tissues, including muscle, liver, heart and in animals. The increase in oxidative stress during exercise and recognition of selenium’s stimulation of antioxidant activity inevitably suggest a relation between selenium and exercise. The present review aims to provide information on selenium metabolism and the relation between selenium and exercise.

Keywords: Selenium, nutrition, metabolism, physical performance, exercise.

Selenium binding to plasma and forms a part of this tissue The major source of selenium is soil, and thus the plants. (Underwood 1977; McDowell et al., 1983). Binding to Selenium, which is transferred from soil to plants, animals the plasma proteins albumin, α1 and α2 globulins and β- and humans through the biological cycle, is consequently lipoproteins, selenium is transported to all body tissues, found in the in trace amounts (Oldfield, 1987; including the kidneys, liver, heart, red and white blood Shamberger 1986). Presence of vanadium, cobalt, cells, pancreas tissues and globulin and particularly sulfates in the soil lowers the rate by (Underwood 1977; Church and Pond 1982; Mills 1970). which living things utilize selenium. The amount of Amount of selenium in the blood varies significantly selenium in arid soil is very low, causing selenium relative to its amount in the . Normal selenium level in deficiency in animals living on arid land (Underwood the plasma ranges between 0.08 and 0.12µg/ml. Besides, 1977). hemoglobin, myoglobin, cytochrome-C have been reported as specific proteins and aldolase and myosin Its absorption, transport and storage have been reported as specific for selenium that Selenium absorption occurs through small intestines, is transported by binding to plasma proteins, albumin in duodenum in particular, by active transport (Church and particular (Mills 1970). Pond 1982; Combs and Combs 1986; Keen and Graham 1989). Selenium as an element and selenium sulfite are Mobilization and excretion of selenium scarcely absorbed (Keen and Graham 1989; Kutsky Selenium is excreted through feces, urine and . 1981). However, selenium which is taken in the organic Its rates of excretion vary according to the animal species, form through diet or converted into organic form by the its route of administration, amount of selenium per ration, organism is easier to absorb, and therefore has higher its chemical form, as well as the levels of elements like rates of absorption (Church and Pond 1982; Combs and arsenic and copper, which promote selenium excretion Combs 1986). Besides, amounts of E and A, as from the body, present in the ration (Underwood 1977). well as ascorbic acid, in the ration increases absorption of Intestinal absorption of selenium taken through oral route selenium (Combs and Combs 1986). After being ranges between 44% and 70%; 14-20% of the intake is absorbed, selenium is rapidly distributed to all bodily excreted through urine and a very small amount through organs and tissues (Keen and Graham 1989). Although skin and respiration in the first week, while 35-55% is selenium transporters have not been definitively disposed of through feces. Injections of arsenic, thallium, classified, it has been noted that it is transported by copper and cadmium increase selenium discharge by respiration, but lead and copper injections do not have any *Corresponding author: e-mail: [email protected] effect on excretion through this route (Underwood 1977). Pak. J. Pharm. Sci., Vol.29, No.5, September 2016, pp.1719-1725 1719 Selenium: Its metabolism and relation to exercise

Daily selenium need and its relation to health selenium in the diet influenced functions of phagocytic Selenium in the diet usually comes from white and red cells (neutrophils, macrophages) (Boros, 1980) and that in , grains and . An adult human body contains neutrophils obtained from rat, mouse 20mg selenium. Selenium which is particularly and cattle had an impairment in their ability not only to concentrated in the liver and kidney is found most phagocytize Candida albicans, but also to kill abundantly in the muscles (Levander, 1986). Amounts of phagocytized Candida albicans (Boyne at al., 1986). It daily selenium intake recommended by health was argued that lysosomal membranes of macrophages organizations are 20-30µg for children (aged 1 to 10), contained GPx and that these were destroyed in selenium 70µg for males over 20 years, 55µg for females, and 65 deficiency (Combs and Combs, 1986). Generally, µg for pregnant women (Van Campen, 1991). It was selenium deficiency produces immunosuppressive results. reported that amount of daily selenium intake in the U.S. However, supplementation of selenium at physiological ranged between 60 and 216µg and in that case, the doses has been reported to be associated with an increase amount of selenium in the blood was in the range between or improvement in the immunological response 190 and 250µg/L (Burk, 1984; Burk 1991). However, in (Kremidjian-Schumacher and Stotzky, 1987). Some New Zealand where selenium deficiency is common, experimental studies conducted on various animal species amount of daily selenium intake was reported to stand at (Dhur et al., 1990) have shown a positive correlation 28-50µg/L, in which case selenium in the blood ranged between level of selenium and resistance against between 50 and 100µg/L. In China, daily selenium intake infectious agents. It was shown that selenium-deficient was reported to be 30µg/L and the selenium in blood was animals with induced experimental infections were very 10µg/L, which is below the normal value (Van Campen, vulnerable against infections. On the other hand, cows 1991). These values indicate that there is a conspicuous and sheep supplemented with selenium were selenium deficiency in China. Selenium deficiency in demonstrated to be very resistant against infectious agents Chinese people was established to be associated with (Dhur et al., 1990). Selenium was also reported to have a basic cereal products’ containing low concentrations of positive contribution to the prevention of subclinical and selenium (Yang et al., 2010). In fact, the significance of clinical mastitis and this contribution was explained by selenium fur human health was first put forward through selenium’s possible stimulating effect on the number of Keshan disease seen in rural China. One- to 10 year-old PMN (polymorphonuclear leukocytes), immune functions children who died due to Keshan disease were found to and antibody production (Babior, 1978). have blood selenium concentrations between 8 and 26µg/L. It was noted in the same study that having blood Symptoms of selenium deficiency in domestic animals selenium concentration in the range between 32 and 83 and humans have been examined in detail. These include µg/L might bring about the risk of premature death due to degenerative disorders in many tissues, defective heart disease (Jackson 1988; Burguera et al. 1995). reproduction and growth, increased susceptibility against Burguera et al., (1995) analyzed selenium in gastric cardiovascular diseases, immune defects and some tissues of healthy individuals, as well as people with (Keen and Graham, 1989). gastritis, ulcer and stomach . Their results demonstrated that selenium concentration in gastric tissue It was noted that presence of 0.05-0.10µg/g and more was 473µg/L in healthy individuals, 355µg/kg in selenium was enough for protection against deficiency individuals with ulcer and 36µg/kg in individuals with syndrome in animals and that the syndrome occurred chronic gastritis. These results show that selenium has an when the amount of selenium was less than 0.05µg/g important role in preventing the development of (Oldfield, 1987; Keen and Graham, 1989). However, it cancerous tissues. Likewise, research about the relation was reported that dietary selenium concentration should between selenium and cancer revealed that physiological be in the range between 0.10 and 0.20µg/g values in order doses of selenium in humans were not carcinogenic and for optimal GPx activity to occur in tissues and that when even had an anti-carcinogenic effect (Oldfield, 1987), and dietary selenium level exceeded 3µg/g, some harmful that there was a negative correlation between mortality effects ensued (Combs and Combs, 1986; Keen and rates of cancer patients and selenium concentrations. Graham, 1989). Toxic dose of selenium in rats was found Although it is known that low levels of selenium 3.35-3.5mg/kg for intraperitoneal selenium (as sodium supplementation to the diet reduce incidence of and selenite) and 3mg/kg for intravenous selenium mortality due to cancer, this topic is still debated (Shamberger, 1986). Changes that occur in the selenium (Shamberger, 1986; Underwood 1977). concentration of the body directly affect , which is the selenium (Neve, 1995). Selenium, which is an essential substance, has an effect It was reported that 12% of the total selenium in the on the immune system. For instance, it plays a central role plasma was bound to glutathione peroxidase (Behne and in the non-specific humoral and cellular immune system Wolters, 1979). (Boyne et al., Kremidjian-Schumacher and Stotzky, 1987). It was reported that changes in the amount of 1720 Pak. J. Pharm. Sci., Vol.29, No.5, September 2016, pp.1719-1725 Abdulkerim Kasim Baltaci et al

Selenoproteins Phospholipid hydroperoxide glutathione peroxidase Selenium is a very important micronutrient of the main (GPx4) metabolism. It accumulates in the active zone of the Phospholipid hydroperoxide glutathione peroxidase proteins’ large area as . Selenium in (GPx4) is defined as a membrane enzyme that is directly selenocysteine is almost ionized in physiological responsible for the reduction of hydroperoxides conditions and thus it is a highly effective biological (Ursini et al., 1985). This enzyme is a monomer and its catalyst (Arthur et al., 1997). It was claimed that there activity is preserved, relative to GPx1, even when might be up to 100 selenoproteins in mammalian systems selenium levels drop (Bermano et al., 1995). GPx4 can (Burk and Hill, 1993); of these, selenoproteins up to 30 interact with both small, soluble hydroperoxides and have been defined as 75Se in systems (Evenson phospholipid hydroperoxides and can also metabolize and Sunde, 1988). Until today, 15 selenoproteins have cholesterol and cholesterol ester hydroperoxides in been classified or cloned in such a way that their oxidized low-density lipoproteins (Weitzel et al., 1990). biological functions have been defined. These are the 4 Consequently, it is reported to be central in the glutathione peroxidase enzymes that represent the major elimination of hydroperoxide. Unless hydroxyl is reduced classes of selenoproteins with functional importance: to fatty acids, it can lead to uncontrollable radical chain Classical GPx1, gastrointestinal GPx2, plasma GPx3 and reactions that damage the integrity of membranes. phospholipid hydroperoxide GPx4. Amount of GPx4 in the tissues does not exactly reflect the distribution activity in animals, and this is Glutathione peroxidases (GPx1) either a reflection of the selenium-specific area dependent Classical glutathione peroxidase (GPx1), is the first on cellular function or else indicates the difference in functional, biochemical determiner of selenium status. It levels of factors activating GPx4. Active or inactive is the strong linear bond between GPx activity and mechanism of the enzyme is not known yet. However, it leukocyte selenium concentration and is the first defined is noted in evidence of its important function in selenoprotein. GPx was reported to act as an antioxidant, membranes differentiating spermatogenic cells that there by directly reducing phospholipase A2 and H2O2, which is certainly a correlation between peroxide levels and are among partitioned lipid hydroperoxides, and to be differentiation (Calvin et al., 1987). found in cell (Rotruck et al., 1973). It can also function as an important mediator for selenium, which Selenium and exercise harbors 4 selenocysteine residues in the tetrameric It is known that strenuous physical exercise triggers acute structure (Burk, 1984). phase immune response and thus forms a defense response against the condition involving reactive Gastrointestinal glutathione peroxidase (GPx2) species (Emre et al., 2004). As in inflammation and Gastrointestinal glutathione peroxidase (GPx2) protects infection, exercise increases body temperature, serum mammals against the harmful effects of lipid cytokines (interleukin 1, interferon α) and circulating hydroperoxides (Chu et al., 1993). In animal studies, leukocytes. Short-term physical exercise can stimulate selenium deficiency increases enzyme activity, but no leukocyte mobilization, thereby increasing the leukocyte such effect has been reported in GPx2 activity in humans. concentration in the circulation. Exhaustive physical Gastrointestinal glutathione peroxidase is the major exercise is known to stimulate oxidative stress probably selenoprotein antioxidant in the colon. Oxidative stress is by stimulating oxidative damage in several tissues pivotal in tumors. Therefore, it has been argued that with including muscle, liver, heart and in animals (Sen its antioxidant function, GPx2 can develop an early and Packer, 2000). Furthermore, a series of defense defense against colon cancer (Brown and Arthur, 2001). mechanisms including SOD ( dismutase) and GPx, as well as other endogenous antioxidants, protect Extra cellular glutathione peroxidase (GPx3) cells against these toxic oxygen (Reddy et al., Extra cellular GPx (GPx3) is another selenoprotein with 1998). Selenium is an acute phase 1 and acute phase antioxidant potential. However, this is not the main task it reactant. That is because its concentration in a systemic fulfills in the plasma. Hybridization studies (Avisssar et inflammatory response was found low (Sattar et al., al., 1984) indicate that GPx3 mRNA (messenger 2001). ribonucleic acid) is formed in proximal albright epithelial cells and that GPx3 can have a specific antioxidant Selenium metabolism in the body can change during function in extra cellular areas or renal tubules, as GSH exercise. This is a type of acute phase responses. In (glutathione) concentration is high in the kidney. It has humans, lactate concentrations increase in response to been argued that other like thyrotoxin can act as increasing exercise (Grant et al., 2002). A negative electron transmitters and support the antioxidant function correlation was shown between pH and lactic acid in of GPx3 in the plasma. GPx3 is a protein disulphide, blood (Rodas et al., 2000). Selenoprotein P is bound more which is important in the regulation of thyrotoxin in endothelial cells in acidosis (Burk et al., 1997). development and antioxidant defenses (Holmgren, 1989). Therefore, the decrease in serum selenium in the post- Pak. J. Pharm. Sci., Vol.29, No.5, September 2016, pp.1719-1725 1721 Selenium: Its metabolism and relation to exercise exercise group may be associated with the transfer of check on post-exercise free radical production can be lactate from the muscle to blood in exercise (Rodas et al., terminated by control mechanisms (Tiidus, 1998). 2000). Several tissues have been reported to secrete extra cellular selenoprotein (extracellular GPx and Reports of the researchers cited above indicate an selenoprotein P) (Anema et al., 1999). Selenoprotein P is inevitable relation between selenium, antioxidant activity related to renal glomeruli and vascular endothelial cells in and exercise. Ji et al., (1988) studied the effect of the brain. In an immunohistochemical study, selenium deficiency on oxidant enzymes in the liver and selenoprotein P was reported to be strongly correlated skeletal muscle in chronic and acute exercise and with endothelial cells. Selenoprotein P is present in the established that selenium deficiency consumed the GPx in extra cellular fluid and binds to cells (Burk et al., 1997). the liver and muscle. It was shown that MDA Definition of some selenoenzymes is regulated by (malondialdehyde) production during physical exercise secondary messenger systems (Anema et al., 1999; Howie was inhibited parallel to the increase in selenium levels as et al., 1998). A negative correlation was found between a result of combined supplementation of selenium, pre-exercise and post-exercise selenium levels. This E and in physical exercise (Kaczmarski negative correlation also applies to the maximal heart et al., 1999). Similarly, it was reported that selenium and rate. It may be associated with heart morphology of supplementation for 6 weeks reduced MDA athletes, as well as the effects of different sports. concentration in aerobic exercise (Kim, 2005). It was Individuals with high heart rates were reported to have argued that combined supplementation of vitamin E and low selenium levels (D’Andrea et al., 2002). It was added selenium was more effective than individual that both serum selenium levels and heart rate were supplementation of each in exercised experimental restored to normal values after 4 weeks of selenium animals (Veera Reddy et al., 1992), while Zamora et al., supplementation (Shu, 1989). Emre and colleagues (2004) (1995) found that selenium supplementation alone could showed similar results, as well. As a chronic result of reduce in acute and chronic exercise. adaptation to training, GPx system is activated (Evelo et al., 1992; Hellsten et al., 1996; Leeuwenburg et al., 1994; There are also conflicting reports about the relation Powers et al., 1994; Tessier et al., 1995). GPx and serum between selenium and exercise. It was reported in a study selenium levels measured in erythrocytes did not vary at that in case of a 10-week endurance exercise, daily any time during extra endurance stress of trained athletes supplementation of 180µg organic selenium did not have (Rokizki et al., 1994). However, antioxidant conditions in any impact on adaptations stimulated by endurance pre- and post-training measurements varied widely in the training (Margaritis et al., 1997). A similar finding to the neutrophils of training individuals (Powers and Ji, 1999). effect that selenium supplementation did not affect Selenium can also be evaluated as a speed-limiting physical performance was put forward by Tessier and molecule in the GPx system. Peroxidase enzyme cannot colleagues (Tessier et al., 1995). Likewise, it was claimed be formed in the absence of selenium and this results in that tiring aerobic exercise caused DNA the endangerment of the antioxidant protection provided (deoxyribonucleic acid) damage and that selenium by the GPx system (Leeuwenburg et al., 1994; Powers et supplementation did not hinder this damage (Davison et al., 1994; Tessier et al., 1995; (Rokizki et al., 1994; al., 2005). By the same taken, Margaritis and colleagues Powers and Ji, 1999; Ohno et al., 1988). Exercise (Margaritis et al., 2005) demonstrated in their study that increases free radical production and GPx activity. erythrocyte GPx activity was not related with selenium. Different researchers aiming to determine GPX activity in various muscle types demonstrated elevated GPx levels. It was reported that intensive swimming exercise in rats These elevations were interpreted by some researchers in significantly inhibited zinc and selenium levels, while relation to the exercise duration, while they were found combined supplementation of zinc and selenium unrelated to exercise duration by others (Powers and Ji, prevented the oxidative stress caused by swimming 1999; Ortenblad et al., 1997). Thus it may be exercise in rat testis tissues (Jana et al., 2008). Yur and hypothesized that endogenous activation of the GPx colleagues (2008) showed that a 7-minute running system by chronic exercise constitutes an adaptive exercise had important effects on serum , mechanism that prevents the formation of free radicals. potassium, copper, and iron/zinc ratio in horses However, as debatable results, decreased glutathione supplemented with vitamin E and selenium. Similarly, it responses have also been reported in individuals. These was demonstrated in a horse study that vitamin E and contradictions may arise from exercise protocols, selenium had a synergic relation in bringing about GPx experimental level, age, sex and genetic factors. Although activation (Kirschvink et al., 2006). That selenium the role of selenium in the post-exercise resting period has deficiency was shown to cause weakening of muscle not been clarified, it is known to have a part in the concentrations in exercising individuals is a remarkable structure of the GSH system. SOD production can be report concerning the relationship between selenium and controlled by antioxidants like the GSH system. The exercise (Milias et al., 2006). It was noted that selenoprotein levels that dropped as a result of selenium 1722 Pak. J. Pharm. Sci., Vol.29, No.5, September 2016, pp.1719-1725 Abdulkerim Kasim Baltaci et al deficiency was correlated with several muscle pathologies Bermano G, Nicol F, Dyer JA, Sunde RA, Beckett GJ, (Hornberger et al., 2003). Arthur JR and Hesketh JE (1995). Tissue-specific regulation of selenoenzyme gene expression during An overall evaluation of our current knowledge on this selenium deficiency in rats. Biochem. J., 311(Pt 2): topic inevitably suggests that there is an important 425-430. relationship between selenium and physical performance Boros DL (1980). Phagocytosis. In: Sonnenwirth AC, (Akil et al., 2011a; Akil et al., 2011b; Akil et al., 2011c). Jaret L, editors. Gradwohl’s Clinical labaratory The effect of selenium on antioxidant activity in particular methods and diagnosis; 8. edition. London. 1249-1256. may foreground this element in the prevention of the Boyne R, Arthur JR and Wilson AB (1986). 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